Project Summary/Abstract (Project 3, Vance) Intracellular pathogens remain a significant global cause of human morbidity and mortality. The overall goal of this Program Project Grant is to characterize the host pathways that specifically detect and eliminate intracellular bacterial pathogens. Project 3 will contribute to this overall goal by focusing on the intracellular gram-negative bacterial pathogen Legionella pneumophila, the cause of Legionnaires' Disease in humans. As in previous iterations of this Program Project Grant, our core strategy is to compare the host responses induced by L. pneumophila to those induced by L. monocytogenes (Project 1) and M. tuberculosis (Project 2). Leveraging these comparisons allows us to identify pathogen-specific responses as well as universal responses induced by diverse intracellular bacterial pathogens. Three aims are proposed. In Aim 1, we test the hypothesis that postranscriptional responses downstream of the STING pathway are important in controlling intracellular bacterial infections. In Aim 2, we test the hypothesis that L. pneumophila specifically targets the mTORC1 pathway. We hypothesize that mTORC1 manipulation liberates host amino acids for bacterial consumption, but also contributes to innate immune responses to the bacterium. Lastly, in Aim 3, we take a broader approach and use comprehensive profiling technologies to identify novel post-transcriptional responses that regulate the host response to L. pneumophila. Our expectation is that by discovering novel host pathways that regulate intracellular bacterial growth and innate immunity, we will identify targets that can be exploited for therapeutic intervention.